COL2A1 – Primary Avascular Necrosis of the Femoral Head

Primary avascular necrosis of the femoral head, primary, 1 is an autosomal dominant skeletal dysplasia characterized by groin pain, hip dislocation, and diminished joint mobility due to compromised type II collagen integrity. The disease (MONDO:0054550) is caused by heterozygous glycine substitutions in the Gly-X-Y repeat of the triple-helical domain of the COL2A1 gene (HGNC:2200) disrupting collagen fibril formation and leading to femoral head osteonecrosis.

In a landmark study, three four-generation kindreds with familial avascular necrosis of the femoral head were shown to harbor heterozygous G→A transitions in COL2A1 exon 50 (c.3508G>A, p.Gly1170Ser) and exon 33 (c.2149G>A, p.Gly717Ser). These glycine-to-serine substitutions co-segregated with disease in all affected members, and haplotype analysis confirmed independent recurrence of the p.Gly1170Ser allele on distinct backgrounds, enabling presymptomatic carrier detection in at-risk relatives (PMID:15930420).

A subsequent report in a Chinese family (n = 45 members) identified a novel heterozygous c.1888G>A (p.Gly630Ser) variant in exon 29 that segregated with either Legg-Calvé-Perthes disease or primary avascular necrosis of the femoral head. Affected individuals exhibited coxa vara and hip dislocation, consistent with loss of triple-helix stability in the Gly-X-Y domain (PMID:24949742).

All pathogenic variants are missense glycine substitutions within the critical Gly-X-Y motif of COL2A1. No loss-of-function or deep intronic variants have been reported for this phenotype. The recurrent nature of p.Gly1170Ser across pedigrees highlights a mutational hotspot rather than a single founder event.

Functional studies demonstrate that replacement of Gly with Ser in the triple-helical domain abolishes proper chain folding, disrupts procollagen secretion, and compromises extracellular matrix assembly. These mechanistic data concord with the clinical phenotype, supporting a dominant-negative effect on cartilage integrity (PMID:24949742).

Integration of genetic and experimental findings across four independent families establishes a Strong gene–disease association. Additional large-scale population studies may further refine penetrance and variant spectrum. Key Take-home: Heterozygous glycine substitutions in COL2A1 Gly-X-Y motifs cause autosomal dominant primary avascular necrosis of the femoral head, informing molecular diagnosis and family counseling.

References

• The New England journal of medicine • 2005 • Type II collagen gene variants and inherited osteonecrosis of the femoral head PMID:15930420
• PLoS One • 2014 • A novel p. Gly630Ser mutation of COL2A1 in a Chinese family with presentations of Legg-Calvé-Perthes disease or avascular necrosis of the femoral head PMID:24949742

Evidence Based Scoring (AI generated)